These studies assessed efficacy and safety of a synthetic peptide-containing surfactant in the treatment of respiratory distress associated with meconium aspiration in rhesus of 150-160 days gestation. Surfactant was prepared consisting of phospholipids and a synthetic peptide modeled after Surfactant Protein B (SP-B). "KL4-Surfactant" contains a peptide having the sequence KLLLLKLLLL-KLLLLKLLLLK. This was selected because it mimics repeating stretches of hydrophobic residues with intermittent basic hydrophilic residues seen in SP-B. Twelve rhesus were treated with one dose of KL4-Sirfactant within 3.3 hours of birth and after a 20% meconium solution was instilled into the lungs with 2IA02 < 10. Arterial to alveolar oxygen partial pressure (a/A) ratio was found to rise froma pre-treatment level of 0.08 1 0.006 (mean 1 SEM), indicatoive of severe pneumonia, to 0.42 1 0.021 at 12-13 hours post-treatment. Oxygenation improvement persisted throughout the study period, with a mean a/A at 22-23 hours of 0.47 1 0.065. Gross and microscopic examination of the lungs and chest radiographs confirmed reversal of the atelectasis seen prior to treatment. Animals treated with200 mg/kg showed faster, more consistent, and greater response than those treated with an average dose of 127 mg/kg. Twelve monkeys treated with ~200 mg/kg and followed 19-24 hours showed no evidence of toxicity as demonstrated by physiologic hematologic, biochemical, and pathologic data. The importance of the peptide in the synthetic surfactant was apparent from results obtained with a control group of two monkeys treated with placebo; the a/A ratio of this group was 0.15 1 0.03 at ten hours of age and radiographs and histology confirmed severe pneumonia, PMN infiltration, and increased IL-8 and mylesperoxidase levels in terminal bronchoalveolar lavage. (Funded, in part, by the R.W. Johnson Pharmaceutical Research Institute).